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Improvement of viral fusion inhibitor enfuvirtide efficacy by conjugation with membrane anchoring lipids
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The human immunodeficiency virus type 1 (HIV-1) is a highly pathogenic and evasive virus, for which no cure has yet been achieved. The majority of the antiretroviral drugs developed over the years against this infection target key enzymes in HIV life cycle, such as reverse transcriptase, integrase and protease. Fusion of viral and host cell membranes is a crucial step in virus infectivity;therefore,the development of viral entry inhibitors has great advantages over conventional drugs, since they prevent the release of the viral content into the host cell. Previous studies showed that the antiviral activity of HIV-1inhibitor peptides is increased bythe addition of cholesterol and polyethylene glycol (PEG). The aim of the present work isto characterizethe interaction of enfuvirtide derived molecules by conjugation with cholesterol,palmitic acid or α-tocopherol as lipid anchors and PEG as spacer, with biomembrane model systems and human blood cells.Fluorescence spectroscopymethodologies, including membrane partition and fluorescence quenching assays,demonstrated that conjugation with lipids increasesthe peptides ability to interact with membranes of different compositions. In addition, the depth of peptide insertion into the membrane was assessed using lipophilic probes, revealing that the conjugated peptides are located in a more shallow position than the unconjugated one. Moreover, dipole potential assays showed that conjugated peptides exhibit a higher affinity towards cholesterol-rich membranes, as well as human blood cells, than the unconjugated peptide.Altogether, the obtained results indicate that a proper balance between membrane affinity and peptide exposure is required in order to enhance antiviral activity. Therefore, the addition of lipid moieties to an established fusion inhibitor such as enfuvirtide can be a promising strategy against HIV-1.
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VIH-1 Fusion inhibitor Enfuvirtide Membrane anchoring lipids